Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial

Tie, J; Agitg Dynamic-Iii Study Group; Wang, Y; Loree, JM; Cohen, JD; Wong, R; Price, T; Tebbutt, NC; Gebski, V; Espinoza, D; Burge, M; Harris, S; Lynam, J; Lee, B; Lee, MM; Breadner, D; Debrincat, M; Foroughi, S; Chantrill, L; Lim, SH; Gill, S; O&#39;Callaghan, C; Ptak, J; Silliman, N; Dobbyn, L; Popoli, M; Bettegowda, C; Papadopoulos, N; Kinzler, KW; Vogelstein, B; Gibbs, P

Author(s): Tie, J; Agitg Dynamic-Iii Study Group; Wang, Y; Loree, JM; Cohen, JD; Wong, R; Price, T; Tebbutt, NC; Gebski, V; Espinoza, D; Burge, M; Harris, S; Lynam, J; Lee, B; Lee, MM; Breadner, D; Debrincat, M; Foroughi, S; Chantrill, L; Lim, SH; Gill, S; O'Callaghan, C; Ptak, J; Silliman, N; Dobbyn, L; Popoli, M; Bettegowda, C; Papadopoulos, N; Kinzler, KW; Vogelstein, B; Gibbs, P;
Details: Publication Year 2025-12,Volume 31,Issue #12,Page 4291-4300
Journal Title: Nature Medicine
Abstract: Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 weeks after surgery and were assigned (1:1) to ctDNA-guided or standard management. In the ctDNA-guided arm, patients negative for ctDNA received de-escalated therapy, whereas ctDNA-positive patients received escalated therapy. Clinicians prespecified the standard regimen. Primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients. Secondary endpoints included treatment-related hospitalization and ctDNA clearance. Among 968 evaluable patients, 702 (72.5%) were ctDNA negative. With a median follow-up of 47 months, ctDNA-negative patients experienced significantly fewer recurrences than ctDNA-positive patients (3-year RFS 87% versus 49%; P < 0.001). In ctDNA-negative patients, de-escalation reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%) but yielded slightly lower RFS than standard management (85.3% versus 88.1%), not meeting the non-inferiority margin. In ctDNA-positive patients, higher ctDNA burden correlated with recurrence risk (3-year RFS 77% to 23% across quartiles; P < 0.001). Escalated therapy did not improve outcomes over standard management (2-year RFS 51% versus 61%). There was no unexpected toxicity. Persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14% versus 79%). ctDNA is validated as a strong prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with outcomes approaching standard of care, whereas exploratory chemotherapy intensification conferred no RFS benefit, suggesting a need for novel strategies in ctDNA-positive disease.Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617001566325 .
Publisher: Springer Nature
Keywords: Humans; *Circulating Tumor DNA/blood/genetics; Male; Female; Middle Aged; Chemotherapy, Adjuvant; *Colonic Neoplasms/drug therapy/genetics/blood/pathology; Aged; Oxaliplatin/administration & dosage/therapeutic use; Neoplasm Recurrence, Local/genetics; Adult; Biomarkers, Tumor/blood/genetics; Neoplasm Staging; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Aged, 80 and over
Research Division(s): Personalised Oncology
PubMed ID: 41115959
Publisher's Version: https://doi.org/10.1038/s41591-025-04030-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-11-03 09:22:08

Last Modified: 2026-01-29 01:41:42